Project Summary As a post-doctoral research fellow, I have been working on several projects related to molecular signaling mechanisms of cardiac hypertrophy and heart failure. My current projects investigate how protein kinases such as apoptotic signal-regulating kinase 1 (ASK1) and TGF2-activated kinase 1 (TAK1) regulate the cardiomyocyte hypertrophic response and apoptosis. These efforts resulted publications in Molecular Cellular Biology 2006 and Nature Cell Biology 2009 in press. Other research projects investigate different roles of protein kinase C (PKC) isoforms in the regulation of cardiac contractility and heart failure propensity, and a manuscript is in revision at Circulation that reveal novel insights into PKC signaling in the heart. The molecular mechanisms that underpin cardiac hypertrophy and its culmination in heart failure is a highly active area of research in our field, and recent work from us and others is revealing a more complicated network of signaling effectors than originally anticipated. For example, my most recent studies show that TAK1 functions as a critical control point for the hypertrophic response through crosstalk with several other signaling pathways such as calcineurin-NFAT, IKK-NF:B, and MAPKs in cardiac myocytes. Here I hypothesize that TAK1 serves as a central regulator of the hypertrophic signaling network in vivo, which will be investigated using cardiac specific TAK1 transgenic and gene targeted mouse models. To examine the hypothesis, three specific aims are proposed: 1) To determine if genetic deletion of TAK1 reduces cardiac hypertrophy in vivo. 2) To determine if activation of TAK1 is sufficient to induce cardiac hypertrophy in the adult heart. 3) To define a potential signaling network between TAK1 and other hypertrophic signaling pathways including calcineurin and NF:B. This approach may suggest novel therapeutic strategies if conclusive proof can be established in animal models implicating TAK1 signaling in the pathogenesis of hypertrophy and/or heart failure. During the first 1-2 years of the mentored phase of this award, I plan to obtain further research experience and knowledge using relevant research and educational resources of the institution, finish up my current research projects, and obtain an independent investigator position. My long term career goal is to establish an independent research program with a focus on molecular mechanisms of cardiac hypertrophy and heart failure. During the independent R00 phase of this award, I will invest most of my time and efforts in my proposed and other new research projects and prepare for subsequent grant support. With regard to research environment, University of Cincinnati together with Children's Hospital provide outstanding infrastructure and collaborators. In fact, the molecular cardiovascular group of scientists here are nationally recognized and highly interactive. The sponsor's laboratory is an ideal environment to foster my career development in cardiovascular biology, with great mentorship. The two-phase career development plan (both mentored and independent) fits well with my career goals and prior experience, which will substantially enhance my research career and allow the pursuit of novel research directions and approaches. PUBLIC HEALTH RELEVANCE: Project Narrative A better characterization of signaling mechanisms is critical for possibly designing novel approaches for treatment of hypertrophic heart diseases. Here we will evaluate how TAK1 signaling regulates cardiac hypertrophy using genetically manipulated mouse models. This approach may suggest novel therapeutic strategies if conclusive proof can be established in animal models implicating TAK1 signaling as a key regulator of hypertrophy and/or heart failure.